IN VIVO FAST SCAN CYCLIC VOLTAMMETRY REVEALS DISTINCT DOMAINS OF DOPAMINE TERMINAL FUNCTION IN THE STRIATUM

摘要

The striatal dopaminergic system regulates several brain functions; movement, cognition, motivation, and reward. As such, failures of this system lead to numerous diseases including Parkinson's disease, schizophrenia, and drug addiction. Dopaminergic neurons communicate with, and regulate the function of, target cells by controlling the extracellular dopamine concentration. Release of dopamine from neuron terminals elevates the extracellular concentration activating pre- and post-synaptic transmembrane receptor proteins. Clearance of dopamine via the dopamine transporter lowers the extracellular concentration, terminating dopamine receptor activation. This dissertation focuses on the role the pre-synaptic dopamine D2-receptor and the dopamine transporter play in the management of extracellular dopamine concentrations, i.e. dopamine signaling.We employ carbon fiber electrodes in conjunction with fast scan cyclic voltammetry to detect changes in the extracellular dopamine concentration during and after electrical stimulation of dopamine neurons. Fast scan cyclic voltammetry is the ideal analytical method to detect dopamine signaling events because it has a high spatiotemporal resolution that can track sub-second changes in extracellular dopamine concentration from small populations of terminals. Pharmacological drugs are used to determine the role of D2-receptor and dopamine transporter proteins in controlling the extracellular dopamine concentration.Our results reveal that differences in dopamine transporter function alter D2-recptor activation, segmenting the striatum into two domains of dopamine terminals; fast and slow. Localized fast domains, which fit the classic model, release dopamine immediately upon stimulation and clear dopamine rapidly following the stimulus. In Slow domains, evoked release is initially inhibited but accelerates as stimulation continues. The rate of dopamine clearance from slow domains is significantly slower. Thus, we redefine the striatal dopamine system, once thought to be homogenous, as a pathway comprised of two distinct domains of dopamine function. These results reveal a previously undiscovered slow domain of dopaminergic activity; changing our understanding of how the striatal dopaminergic system regulations brain function, and providing new insights into the causes of, and therapies for, dopaminergic pathologies.